Urinary Glycosaminoglycan Levels Are Increased in Acute Severe Asthma – a Role for Eosinophil-Derived Gelatinase B?

Asthma Extracellular matrix Proteoglycans Glycosaminoglycans Matrix metalloproteases Eosinophils Correspondence to: Dr. Janis K. Shute, Immunopharmacology Group (825), Level F, Centre Block, Southampton General Hospital, Southampton SO16 6YD (UK) Introduction Remodelling of the subepithelial matrix of the bronchi is a feature of mild to severe asthma [1]. Proteoglycans are important structural and functional components of the extracellular matrix, pericellular and basement membranes [2]. These macromolecules influence cell adhesion, migration and proliferation, properties which largely depend on the nature of the glycosaminoglycan (GAG) side chains. Degradation of proteoglycans is via the concerted action of heparanases and proteases [3] ‚ in particular neutrophil elas-tase and the matrix metalloproteases [4, 5]. The principal substrates for matrix metalloprotease-9 (92-kD gelatinase B) are collagens IV and V and the proteoglycans. Gelatinase B is activated by proteolytic degradation and inhibited by tissue inhibitor of metalloproteases-1 (TIMP-1). Although eosinophils from a patient with squamous cell carcinoma were reported to express gelatinase B [6], others reported little [7] or no [8] enzyme in normal eosinophils. In a rat model of pulmonary emphysema [9] ‚ elastase instilled into the airways induced the release of the GAG side chains from alveolar heparan sulphate proteoglycan. A decrease in the GAG content of the lung was reflected in an increase in urinary GAG levels. In this study, we investigated the concentration ofGAGs in the urine from patients with both acute and stable asthma for comparison with normal samples. We further sought evidence for the involvement of eosinophil-derived gelatinase B and TIMP-1 in tissue remodelling in asthma. Materials and Methods Urine samples were collected from normal individuals, patients with stable severe asthma and patients admitted to Southampton General Hospital for exacerbation of their asthma symptoms (mean peak flow < 45% predicted). Early morning mid-stream samples were collected and frozen at -20°C prior to analysis. Serum creatinine was measured colorimetrically by the